Abstract Genomic instability is a hallmark of cancer and an enabling feature that facilitates tumor development and advancement to malignancy. The p53 tumor suppressor is known to play a major role in the stabilization of the genome, however, the mechanism by which p53 executes it's function as "guardian of the genome" is unclear. In preliminary studies we have determined that 14-3-3gamma, a protein known to interact with the p53 tumor suppressor, can cause a form of chromosome instability that leads to polyploidy and replication of DNA in the absence of chromosome segregation suggesting that 14-3-3gamma can suppress the spindle activation checkpoint (SAC). Interestingly, we find that wild- type p53 can suppress 14-3-3gamma protein levels and that elevated levels of 14-3-3gamma protein correlate with mutant p53 in human tumors implying that these two proteins have a functionally important interaction. This combined with our observations that 14-3-3gamma acts as an oncogene in rodent cell transformation assays lead us to hypothesize that 14-3-3gamma is an oncogene that leads to genomic instability and that its oncogenic activity is suppressed by wild-type p53. To address this hypothesis we propose conducting the following three specific aims;(1) identify the mechanism through which 14-3-3 acts as an oncogene by creating chimeric proteins between 14-3-3gamma and 14-3-3sigma which have diametrically opposed biological functions, (2) test the hypothesis that 14-3-3 promotes genomic instability by interfering with the spindle activation checkpoint (SAC) which leads to polyploidization, and (3) Test whether overexpression of 14-3-3gamma promotes lung tumorigenesis or enhances chemical induced tumorigenesis in the mouse lung.